Accumulation of agents, such as proteins, lipids, bacteria, viruses, parasites or particles, leads to, or is associated with, pathological conditions. For example, nucleolin, a protein normally expressed in the nucleus or the cytoplasm has been shown to be expressed at the cell surface in neoplastic cells and endothelial cells of angiogenic vessels in vivo. Mi Y, et al. Apoptosis in leukemia cells is accompanied by alterations in the levels and localization of nucleolin. J Biol Chem 278:8572-9 (2003); Sven C, et al. Nucleolin Expressed at the Cell Surface is a Marker of Endothelial Cells in Angiogenic Blood Vessels, Journal of Cell Biology, Vol. 164, No. 4, 871-878 (2003). Another example is P-glycoprotein (P-gp), a plasma membrane protein, which is over expressed in tumor cells that present a multidrug resistance (MDR) phenotype, which causes efflux of several structurally unrelated therapeutic drugs used for cancer treatment. Loo T W, et al. Identification of Residues in the Drug Translocation Pathway of the Human Multidrug Resistance P-glycoprotein by Arginine Mutagenesis, Journal of Biological Chemistry, Vol. 284, No. 36, 24074-24087 (2009). Deposition and subsequent accumulation of intracellular protein aggregates has been observed in several neurodegenerative disorders, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and huntingtin in Huntington's diseases, and prion protein (PrP) in transmissible prion encephalopathies. Brandin P, et al. Prion-Like Transmission of Protein Aggregates in Neurodegenerative Diseases, Nat Rev Mol Cell Biol. Vol. 11, No. 4, 301-307 (2010). Poly A binding protein (PABP) accumulates in the cytoplasm of beta herpesviruses (HCMV)-infected cells. Perez C, et al. Translational control of cytoplasmic poly A binding protein (PABP) abundance in HCMV-infected cells, J Virol. Oct. 27 (2010) Epub.
Intracellular lipids accumulation is commonly observed in advanced atherosclerotic plaques. Monocyte infiltration in the intima layer of the vascular wall is followed by differentiation into macrophages, which in turn take up modified lipoproteins and become macrophage foam cells as a result of such intracellular lipids accumulation. Persson J, et al. Interleukin-1 beta and tumour necrosis factor-alpha impede neutral lipid turnover in macrophage-derived foam cells, BMC Immunology, 9(7) (2008). Obesity is associate with the accumulation of lipids in fat cells.
Some bacteria may accumulate inside cells, for example Mycobacterium tuberculosis and Pseudomonas aeruginosa. M. tuberculosis causes the formation of hard nodules or tubercles in the lungs, parasitizes macrophages by blocking the phagosome-lysosome fusion, a process called phagosome maturation arrest, and by replicating inside the phagosome. Vergne I, et al. Cell Biology of Mycobacterium tuberculosis Phagosome, Ann Rev Cell Dev Biol., Vol. 20, 367-94 (2004). Similarly, P. aeruginosa colonizes the lungs of patients with cystic fibrosis and produces biofilms, alginates, and specific lipid A modifications, which allow the bacteria to escape immune response and cause severe chronic inflammation. Moskowitz S M, et al. The Role of Pseudomonas Lipopolysaccharide in Cystic Fibrosis Airway Infection, Subcell Biochem., Vol. 53, 241-53 (2010). Production of biofilms by Haemophilus influenzae, Streptococcus pneumoniae, and other bacteria, has been linked to chronic otitis media in pediatric patients. Hall-Stoodley L, et al. Direct Detection of Bacterial Biofilms on the Middle-Ear Mucosa of Children With Chronic Otitis Media, JAMA, Vol. 256, No. 2, 202-11 (2006).
Some protozoan parasites present intracellular accumulation, for example Plasmodium, Leishmania, Trypanosoma and Toxoplasma. Plasmodium, the agent causing malaria, replicates and accumulates inside erythrocytes, provoking cell rupture and dissemination of the agent, while the main sites of sequestration of the infected erythrocytes containing the trophozoites, schizonts and gametocytes of the parasite have been shown to be the lung, spleen, and adipose tissue, but also the brain, skin, bone marrow, and skeletal and cardiac muscle. Franke-Fayard B, et al. Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?, PLoS Pathogens, Vol. 6, No. 9, e1001032 (2010). Similarly, Leishmania mexicana and Trypanosoma cruzi reside and proliferate inside macrophages. Zhang S et al. Delineation of Diverse Macrophage Activation Programs in Response to Intracellular Parasites and Cytokines, PLoS Negl Trop Dis, Vol. 4, No. 3: e648 (2010).
Viruses replicate in the host cell, and the accumulation of the viral particles may result in changes to the plasma membrane. Examples include HIV, hepatitis C and rhinovirus. Ma Y, et al. NS3 helicase domains involved in infectious intracellular hepatitis C virus particle assembly, J Virol. 82 (15) 7624-39 (2008); Korant B D, Butterworth B E, Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides, J Virol. 18(1):298-306 (1976).
Ultrasound is a technique that may be used to destroy or induce apoptosis of cells. U.S. Pat. No. 6,821,274 (2004). The technique has been used to selectively remove or kill cells based on differences is the membrane stiffness, such as that caused by cross-linking from AGE-modification. The ultrasound is targeted to harmonic frequencies of the cross-linked cell membranes or components. International Publication No. WO2009/143411 (2009).